Pharmaceutical preparations, fertilizers, herbicidal preparations as well as diagnostic preparations typically comprise one or several excipients, in addition to the active substances, such as therapeutic substances or drugs, fertilizers, herbicides or reagents. Excipients make the manufacturing of the above mentioned products more feasible and give them suitable physicochemical, biological and biopharmaceutical properties. Excipients are used e.g. to facilitate flowability of powder mass. Other reasons are to adjust the weight uniformity and to minimize the dose variation of single dose preparations. Excipients are also used to optimize the energy consumption as well as to enhance the manufacturing rate during production.
A typical stage in the process of manufacturing solid preparations, e.g. pharmaceutical solid dosage forms, especially tablets are the compression techniques, whereby powder mass comprising the active substance/substances and excipient/excipients are densified under high pressure in order to obtain a compact with low porosity, e.g. a tablet. Because most active substances, especially drugs, are typically poorly compressable materials, they are not as such feasible for the formation of firm tablets. Thus, excipients with more favourable compressibility are added to enhance the formation of mechanically strong tablets. Commercially available excipients, for example several types of celluloses, lactoses and dicalcium phosphates can be used for said purpose in tablets.
In addition to the active substance/substances several, chemically and physically different excipients must be used in the preparations. Unfortunately, they beside making the manufacturing possible, also multiply the incompatibility risks between active substance/substances and excipients in the formulations. Incompatibilities may induce chemical and physical instability and thus shorten the shelf life of the product. This is the reason why the trend today is to use as few excipients in formulations as possible.
Granulation of powder mass is a preferred preprocess prior to compression. In a first granulation step the powder mass can be wetted either with water or with liquid binder solutions. This step is followed by a second step, which comprises aggregation of the wet and sticky powder mass. Using said procedure the particle size of the powder mass is increased. The drying process is a typical third and separate step of preprocessing. Another possible granulation method is the slugging or compaction granulation. In this process the powder mass is, firstly, compacted to form slugs, large tablets or compressed plates which are, secondly, crushed to suitable particle size for tabletting. On the other hand, using the direct compression of powder mass without granulation it is possible to accelerate and simplify the tableting process as well as to decrease the energy consumption in manufacturing of tablets. The direct compression process is possible to perform only with free flowing, easily compactable and well compressable powder masses.
Compression of powder mass is done in a tablet press, more specifically in a steel die between two moving punches. Prior to compression, the powder mass should flow into the die. The easiness and steadiness of the flow process and thus the homogenous filling of the die determines the weight and content variation of the compressed tablets as well as the repeatability of the administered doses during drug therapy. The most important variable in the tableting process is the compressional pressure, which densifies the powder mass into a dense compact in the die and thus induces bonding inside the compact and formation of strong tablets. There is often a clear correlation between compressional pressure and mechanical strength of the tablets. The proper mechanical strength is an essential property affecting the easiness of packing, transportation, storing as well as administration of tablets. Furthermore, the mechanical strength is correlated with the disintegration of pharmaceutical tablets in gastrointestinal tract and also with release rate of active substance from the dosage form.
Only few commercial excipients are well adapted for slugging or direct compression. The release of the active substance from the tablet is the most critical phenomenon in which the excipients can have remarkable modifiable effects. Suitable excipients may induce controlled release, most often sustained release of active substance from the tablet. Thus, it is possible to affect the absorption properties, rate and site, as well as the level of achieved drug concentration in blood during drug treatment. This is of uttermost importance both in prophylactic and symptonous medication.
Several possible mechanisms are used to achieve controlled release properties in solid dosage forms. Most often compressed tablets are coated in a separate coating process with polymer films. Although this method is appropriate for achieving suitable drug release properties, several disadvantages are involved in the coating processes. The multistage process, including separate tabletting and coating phases with numerous and complicated process variables is highly energy consuming. Although, water is the solvent of choice, even nowadays organic solvents are often used in coating processes. The evaporation of solvents and their possible harmful effects on tablet structure may also restrict the usability of this technique. The controlling and repeatability of the whole manufacturing chain is especially complicated. Often difficulties may arise due to breaking or inhomogenity of a thin coating film. Thus the drug content can be released much more fastly than desired.
It is also known to prepare controlled release preparations by compressing formulations containing matrix forming excipients. Matrix forming substances commercially available include e.g. methacrylate resins, polyvinyl alcohol, polyethylene glycols. Under compression these substances undergo softening, plastic deformation or even melting. Typically the matrix formers are poorly flowing, sticky and smeary substances. Granulation is often an inevitable preprocess prior to compression of formulations containing these substances. Direct compression of these substances in manufacturing scale is hardly possible. Direct processable matrix formers would be important in respect to time and energy saving as well as to better controlling of the whole manufacturing chain. The manufacture of controlled release formulations using a direct compression process is in principle a simple and easily controllable process. Several disadvantageous process factors, e.g. granulation, drying of granules, usage of organic solvents, drying of solvents, can be avoided.
In tableting processes an intact matrix tablet is formed, in which active substance/substances are dispersed. The matrix former should melt, i.e. undergo softening or plastic deformation under pressure. The structure of the matrix affects the release of the active substance from the matrix tablet. Wettability of tablet surface, penetration of gastric fluids into the tablet matrix, dissolution of the active substance inside the matrix as well as diffusion of the dissolved substance out from the matrix are all dependent on the chemical, physicochemical and mechanical structure of the matrix tablet. In addition to the properties of matrix former/formers, the process variables during the manufacturing process also affect the structure of the matrix tablet as well as the biopharmaceutical properties of the preparation.
The controlled release of the active substances from the preparation is especially important in the administration of the therapeutical substances, i.e. the drugs. If the biological half life of the drug is short, the administration in a controlled release dosage form can lengthen the dosing intervals, thus, enhancing the patient compliance toward drug therapy. Furthermore, the sustained absorption of the drug from the controlled release dosage form maintains the drug concentration in blood in a more steady level and thus the harmful fluctuations in concentrations as well as drug response can be avoided. The use of controlled release dosage forms decreases also the drug amount in contact with the biological membranes at a certain moment of time. This is important e.g. for administration of drugs with an irritating effect.
A constant rate of drug release from a controlled release dosage form is usually desired. On the other hand, in some cases a relatively large loading dose just after administration followed by slower, typically constant drug release as a maintaining dose is desired. In some special cases the slow initial release followed by accelerated release is the profile of choice. This is advantageous, if the drug substance is unstable in the stomach, but more resistant in the intestine. Some drugs are also more effectively absorbed e.g. in colon. The modified release profiles might be beneficial also in diseases with symptoms appearing only at day or night time.
As a conclusion, the desired release profile of the administered drug is dependent on the drug substance and the disease. It is beneficial, if the widely modifiable release properties can be produced using a simple manufacturing procedure and simple construction of preparation consisting of few excipients. Although, the above mentioned text mainly deals with pharmaceutical dosage forms, especially tablets, the same properties are important also for fertilizer, herbicidal and diagnostic preparations.